Lyme disease is a multisystem illness caused by infection with the spirochete Borrelia burgdorferi and it is the leading vector-borne disease in the United States. Lyme disease is also common in Europe and also occurs in Russia, China and Japan. In humans, B. burgdorferi infection causes infection primarily in the skin, nervous system, heart and joints. Lyme disease can usually be treated successfully with antibiotic therapy, with the best results seen in patients with early disease. Unfortunately, some patients may not have a complete response to therapy. We currently have three clinical protocols studying patients with Lyme disease. Two protocols are natural history studies and serve as the basis for multiple lines of investigation. One protocol addresses patients with post Lyme disease syndrome. The other protocol allow for the study of patients with classical Lyme disease. A third protocol examines the host reponse in skin biopsies from patients with erythema migrans lesions using microarrays. Our work addresses 3 areas in Lyme disease: laboratory diagnosis, clinical manifestations and immunological responses to B. burgdorferi. We also have a protocol to investigate the cause of Southern Tick-Associated Rash Illness (STARI), in collaboration with the CDC. STARI is a rash similar to the rash of Lyme disease that occurs in persons residing in southeastern and south-central states and is associated with the bite of the lone star tick, Amblyomma americanum.